美国圣犹达儿童研究医院Ben Youngblood团队近期取得重要工作进展，他们研究提出抗肿瘤祖细胞耗尽的CD8⁺ T细胞通过TCR参与得以维持。相关研究成果2024年5月30日在线发表于《自然—免疫学》杂志上。

据介绍，抗肿瘤免疫反应的持久性部分由祖细胞耗尽的CD8⁺ T细胞（Tpex）的持久性介导。Tpex作为补充效应T细胞的资源，并通过自我更新来保持其数量。然而，在持续抗原暴露的情况下，T细胞受体（TCR）的参与如何影响Tpex的自我更新能力尚不清楚。

使用Lewis肺癌模型，该模型在CD8⁺ T细胞中引发最佳或减弱的TCR信号传导，以表明肿瘤引流淋巴结中Tpex的形成及其在肿瘤内的持久性取决于最佳的TCR参与。减弱的TCR刺激加速了最佳启动的Tpex的末端分化。这种TCR增强的Tpex发育和自我更新与树突细胞的近端定位和表观遗传学印迹相结合，涉及Egr2和Tcf1靶位点染色质可及性的增加。

总之，本研究强调了TCR参与在肿瘤进展过程中维持Tpex的关键功能。

附：英文原文

Title: Antitumor progenitor exhausted CD8+ T cells are sustained by TCR engagement

Author: Lan, Xin, Mi, Tian, Alli, Shanta, Guy, Cliff, Djekidel, Mohamed Nadhir, Liu, Xueyan, Boi, Shannon, Chowdhury, Partha, He, Minghong, Zehn, Dietmar, Feng, Yongqiang, Youngblood, Ben

Issue&Volume: 2024-05-30

Abstract: The durability of an antitumor immune response is mediated in part by the persistence of progenitor exhausted CD8+ T cells (Tpex). Tpex serve as a resource for replenishing effector T cells and preserve their quantity through self-renewal. However, it is unknown how T cell receptor (TCR) engagement affects the self-renewal capacity of Tpex in settings of continued antigen exposure. Here we use a Lewis lung carcinoma model that elicits either optimal or attenuated TCR signaling in CD8+ T cells to show that formation of Tpex in tumor-draining lymph nodes and their intratumoral persistence is dependent on optimal TCR engagement. Notably, attenuated TCR stimulation accelerates the terminal differentiation of optimally primed Tpex. This TCR-reinforced Tpex development and self-renewal is coupled to proximal positioning to dendritic cells and epigenetic imprinting involving increased chromatin accessibility at Egr2 and Tcf1 target loci. Collectively, this study highlights the critical function of TCR engagement in sustaining Tpex during tumor progression.

DOI: 10.1038/s41590-024-01843-8

Source: https://www.nature.com/articles/s41590-024-01843-8